microRNA-449a reduces growth hormone-stimulated senescent cell burden through PI3K-mTOR signaling

Abstract

Cellular senescence, a hallmark of aging, has been implicated in the pathogenesis of many major age-related disorders, including neurodegeneration, atherosclerosis, and metabolic disease. Therefore, investigating novel methods to reduce or delay the accumulation of senescent cells during aging may attenuate age-related pathologies. microRNA-449a-5p (miR-449a) is a small, noncoding RNA down-regulated with age in normal mice but maintained in long-living growth hormone (GH)-deficient Ames Dwarf (df/df) mice. We found increased fibroadipogenic precursor cells, adipose-derived stem cells, and miR-449a levels in visceral adipose tissue of long-living df/df mice. Gene target analysis and our functional study with miR-449a-5p have revealed its potential as a serotherapeutic. Here, we test the hypothesis that miR-449a reduces cellular senescence by targeting senescence-associated genes induced in response to strong mitogenic signals and other damaging stimuli. We demonstrated that GH downregulates miR-449a expression and accelerates senescence while miR-449a upregulation using mimetics reduces senescence, primarily through targeted reduction of p16 Ink4a , p21 Cip1 , and the PI3K-mTOR signaling pathway. Our results demonstrate that miR-449a is important in modulating key signaling pathways that control cellular senescence and the progression of age-related pathologies.

MiR-449a: A Potential Biomarker for Vocal Function Preservation in Combination Therapy for Laryngeal Cancer

“…Additionally, in the case of head and neck squamous cell carcinoma, low levels of miR-449a have been linked to a poor prognosis, highlighting its potential as a prognostic marker. These findings are promising and suggest that miR-449a could be a valuable target for cancer treatment [9,12,13].…”

“…This is significant in cancer treatment, as the main objective is to eliminate cancer cells and restore the normal functioning of tissues. The versatile nature of miR-449a makes it a highly promising candidate for developing effective cancer therapies [9].…”

The Molecular Mechanisms in Senescent Cells Induced by Natural Aging and Ionizing Radiation

“…Targets SIRT1 and reduces its expression, leading to the activation of p53 and induction of cellular senescence [83] It is actively expressed in cardiac cells of aged mice, and inhibition or deletion reduces age-associated cardiomyocyte death [84] Increased expression in H2O2-induced premature cellular senescence [85] miR-21 ↑ Overexpression reduces the replicative lifespan of HUVECs [86] miR-146a miR-106a ↓ Five models of cellular senescence show reduced expression [92] miR-17-92 ↓ Increased expression in primary human fibroblasts inhibits Ras-induced cellular senescence [97] miR-15a ↓ Involved in the regulation of stress-induced senescence of WI-38 cells [96] miR-144 ↑ Increased expression in aged erythrocytes from type 2 diabetic patients [98] miR-494 ↑ Overexpression enhances DNA damage and cellular senescence in IMR90 cells [82] miR-449a ↓ Increased expression slows senescence in HUVECs and adipose tissue by targeting p16 Ink4a , p21 CIP1 , and the PI3K-mTOR signaling pathway [99] miR-17 ↓ All seven models of cellular senescence show reduced expression [92] miR-25 ↓ Downregulation in Ras-induced senescent WI-38 cells [96] miR-431 ↑ Increased expression in both replicative and stress-induced senescent human lung fibroblasts [96] miR-34a, a key regulator of SIRT1, is one of the major miRNAs involved in cellular senescence [83]. A positive feedback loop exists between miR-34a, SIRT1, and p53 where p53 activates miR-34a expression, which targets and represses SIRT1, preventing SIRT1mediated deacetylation of p53, thus promoting p53 activity [80].…”